Oxaprotiline, a noradrenaline uptake inhibitor with an active and an inactive enantiomer

The new antidepressant drug, oxaprotiline, and its two enantiomers were investigated with respect to their effects on noradrenaline (NA) and serotonin (5-HT) uptake in vitro and in vivo after acute and repeated treatment. Moreover, the alpha-adrenolytic effects in vitro were also studied. Oxaprotiline proved to be a highly potent and selective inhibitor of NA uptake in rat synaptosomal preparations in vitro and in the rat heart and brain in vivo The NA uptake-inhibiting properties were found to be confined entirely to the (+)- or S-enantiomer: (−)- or R-oxaprotiline, the absolute configuration of which corresponds to that of the naturally occurring (−)-NA, was about 1000 times less potent than the (+)-form in vitro, and was inactive in vivo at doses exceeding the ED 50 of the latter 100-fold. The selectivity of oxaprotiline with respect to NA uptake inhibition was retained after 10 daily administrations. No sign of cumulation or attenuation of the effect was evident. No uptake-inhibiting effect of (−)-oxaprotiline appeared after 10 daily administrations of high doses, indicating that no racemization occurred in the organism. The α 1-adrenoceptor antagonistic effect of oxaprotiline, as determined by the ability to displace [ 3H]prazosin, was in the range of that of imipramine, the (−)-enantiomer being somewhat more potent than the (+)-form. In contrast to imipramine, oxaprotiline was devoid of α 2-adrenoceptor antagonistic effects, as judged by the ability to affect the impulse-related release of [ 3H]NA from rat cortical slices. Since oxaprotiline proved to be an effective antidepressant, clinical testing of its two enantiomers might be helpful with respect to the validation of the catecholamine hypothesis of depression. Moreover, in animal studies, they might help to determine which effects of antidepressants are related to NA uptake inhibition and which are not.